Germline and somatic mutations in tyrosine phosphatase Ptpn11 (Shp2) have recently been identified in the developmental disorder Noonan syndrome and various childhood leukemias, such as juvenile myelomonocytic leukemia (JMML), B-cell acute lymphoblastic leukemia (B-ALL), and acute myeloid leukemia (AML). These mutations cause hyperactivation of Shp2 catalytic activity. Studies in our laboratory and others have demonstrated that a single disease mutation in Ptpn11 is sufficient to cause Noonan syndrome and JMML-like myeloid proliferative disease in mice followed by malignant progression to acute leukemias, suggesting that over activation of Shp2 plays a causal role in these diseases. Direct connection between activating mutations of Ptpn11 and Noonan syndrome and childhood leukemias indicates that Shp2 may be a useful target of mechanism-based therapeutics for preventing/treating hematologic malignancies in Noonan syndrome. Our broad, long-term objective is to determine the molecular mechanisms by which Ptpn11 activating mutations induce Noonan syndrome and childhood leukemias and to use the information gathered to develop novel therapeutics for these diseases. The specific aim of the proposed project is to validate the Shp2 inhibitors, including a clinically used natural product drug identified in our laboratory in suppressing Ptpn11 activating mutation-positive leukemia cells. Both a mouse model of Ptpn11-associated leukemias and JMML patient bone marrow cells will be tested. It is anticipated that this work will establish the rationale for using Shp2 inhibitors to prevent and treat hematologic malignancies in Noonan syndrome. These studies will greatly facilitate the translation of our laboratory finding, i.e., a known clinically used drug as a Shp2 inhibitor, to a clinical trial.